The present invention relates to processes for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine which is useful as an intermediate in the preparation of certain therapeutic agents. In particular, the present invention provides a process for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
The general processes disclosed in the art for the preparation of (2R, 2-alpha-R)-4-benzyl-2-[1-[3,5-bis(trifluoro-methyl)phenyl]ethoxy-1,4-oxazin-3-one result in relatively low and inconsistent yields of the desired product (see U.S. Pat. No. 5,719,147). In contrast to the previously known processes, the present invention provides more practical and economical methodology for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy-3-(4-fluorophenyl)-1,4-oxazine in relatively high yield and purity.
It will be appreciated that (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoro-methyl) phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine is an important intermediate for a particularly useful class of therapeutic agents. As such, there is a need for the development of a process for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis (trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine which is readily amenable to scale-up, uses cost-effective and readily available reagents and which is therefore capable of practical application to large scale manufacture.
Accordingly, the subject invention provides a process for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine via a very simple, short, relatively inexpensive and highly efficient synthesis.
The novel process of this invention involves the synthesis of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine. In particular, the present invention is concerned with novel processes for the preparation of a compound of the formula: 
This compound is an intermediate in the synthesis of compounds which possess pharmacological activity. In particular, such compounds are substance P (neurokinin-1) receptor antagonists which are useful e.g., in the treatment of psychiatric disorders, inflammatory diseases, and emesis.
The present invention is directed to processes for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine of the formula: 
An embodiment of the general process for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine of the formula: 
comprises:
(1) contacting a compound of the formula: 
xe2x80x83with an oxidizing agent to give a compound of the formula: 
(2) activating such compound with an activating agent and contacting the activated compound with ethanolamine to give a compound of the formula: 
xe2x80x83(3) condensing such compound with glyoxal and 4-fluoroboronic acid to give a compound of the formula: 
xe2x80x83(4) intramolecular coupling of such activated compound to give a compound of the formula: 
xe2x80x83(5) quarternizing the amino group of such compound to give a compound of the formula: 
xe2x80x83(wherein Xxe2x88x92 is a counterion)
xe2x80x83(6) hydrolysis of such compound to give a compound of the formula: 
xe2x80x83and (7) hydrogenation of such compound to give the compound of the formula: 
A specific embodiment of the process for the preparation of (2R, 2-alpha-R, 3 a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine of the formula: 
comprises:
(1) contacting a compound of the formula: 
xe2x80x83with an oxidizing agent selected from osmium tetroxide/N-methyl morpholine to give a compound of the formula: 
xe2x80x83(2) activating such compound with an activating agent selected from methanesulfonyl chloride and contacting the activated compound with ethanolamine to give a compound of the formula: 
xe2x80x83(3) condensing such compound with glyoxal and 4-fluoroboronic acid to give a compound of the formula: 
xe2x80x83(4) intramolecular coupling of such activated compound under Mitsunobu conditions to give a compound of the formula: 
xe2x80x83(5) quarternizing the amino group of such compound with a benzyl halide to give a compound of the formula: 
xe2x80x83(wherein Xxe2x88x92 is a counterion)
(6) hydrolysis of such compound with an inorganic base to give a compound of the formula: 
xe2x80x83and (7) catalytic hydrogenation of such compound with a palladium catalyst to give the compound of the formula: 
Another embodiment of the present invention concerns a process for the preparation of a compound of the formula: 
which comprises hydrogenation of a compound of the formula: 
to give the compound of the formula: 
In this embodiment it is preferred that the hydrogenation is catalytic hydrogenation. It is preferred that the hydrogenation catalyst is a palladium catalyst, such as selected from: palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate, palladium on silica, and palladium hydroxide on carbon (Pearlman""s catalyst). It is more preferred that the hydrogenation catalyst is palladium on carbon, especially 5% or 10% palladium on carbon. It is preferred that the solvent for the hydrogenation comprises a solvent which is selected from the group of C1-C4 primary, secondary and tertiary alcohols, and water. Preferred solvents for the hydrogenation comprise methanol, ethanol, isopropanol, n-propanol, n-butanol, water, and mixtures thereof. More preferred solvents for the hydrogenation comprise ethanol or methanol and mixtures thereof with water. It is preferred that the temperature of the reaction mixture for the hydrogenation is from about 10xc2x0 C. to about 50xc2x0 C., wherein the most preferred temperature is about 20-25xc2x0 C. It is preferred that the pressure of hydrogen during the hydrogenation is from about 1 to about 150 psi, wherein the most preferred pressure is about 5 to about 50 psi.
Another embodiment of the process for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-5 oxazine of the formula: 
comprises the processes as outlined in the following Scheme. 
Another embodiment of the present invention is directed to the processes as outlined in the following Schemes.
As depicted in Scheme 1, a retrosynthetic analysis of 1 indicates a possible disconnection at the acetal center leading to 3,5-bis(trifluoromethyl)-sec-phenethyl alcohol 3 and the activated morpholine 2. Unfortunately, this glycosidation-type approach fails because either facile elimination of the leaving group (LG) or substitution from the xcex2-face resulted in the undesired trans stereochemistry, presumably due to steric blocking by the adjacent 4-fluorophenyl group. Alternatively, vinyl ether 4 is a desirable intermediate because diastereoselective hydrogenation of the vinyl ether provides (2R-cis)-2-[[1-[3.5-bis(trifluoromethyl)phenyl]ethenyl]oxy]-3-(4-fluorophenyl)-4-(phenylmethyl)-mopholine (Hale, et al., J. Med. Chem. 1998, 41, 4607.) Importantly, 4 is retrosynthetically transformed to the bicyclic quaternary ammonium salt 5 by a regioselective Hofmann elimination. The critical cis-stereochemistry in 5 is set by an intramolecular displacement of the lactol hydroxyl group of 6, thus overcoming the bias towards the trans arrangement. Lactol 6 is derived from chiral aminodiol 7 using a Mannich boronic acid condensation. It was imperative to the success of this strategy that the single stereocenter of aminodiol 7 controls both stereocenters in the morpholine ring of 6.
Synthesis of aminodiol 7 in racemic or enantiomerically pure form is achieved using known chemistry. A Sharpless asymmetric dihydroxylation of 3,5-bis(trifluoromethyl)styrene (8) set up the necessary absolute stereochemistry and subsequent selective activation of the primary alcohol as the mesylate followed by displacement with ethanolamine lead cleanly to crystalline 7. A three-component condensation is then utilized to assemble the core morpholine ring system in one step from 7.
As depicted in Scheme 2, heating 7 with 4-fluorophenylboronic acid (9) and aqueous glyoxal affords a mixture of lactol diastereomers: 6, 10 and 11 (50:10: less than 2 area %) and regioisomers 12 and 13 (10 and 20 area %), respectively. A chromatographically isolated mixture of 10 and 11 returns to the initially observed isomeric mixture of 6, 10, 11, 12 and 13 by addition of DBU, cat. H3PO4 or by simple heating. This facile equilibration of the isomers in solution, coupled with a crystallization of the desired diastereomer, leads to a crystallization-induced transformation that funnels the complex mixture into a single crystalline isomer. This crystallization induced asymmetric transformation was first demonstrated in the racemic series by seeding the mixture of 6, 10, 11, 12 and 13 with crystalline rac-6 to afford the desired rac-6 in 65% yield (90 A %).
As depicted in Scheme 3, repeating the boronic acid condensation with (S)-7, provides the expected ratio of isomers in solution. However, attempts to crystallize enantiomerically-pure trans lactol 6 were unsuccessful and resulted in the isolation of a minor component of the reaction. mixture, the cis lactol 11. Pure 11 is obtained in 86% yield by slow crystallization of the reaction mixture from methylcyclohexane. Because the trans lactol 6 is the thermodynamically preferred species in solution, brief exposure of a solution of the cis lactol 11 to a trace amount of H3PO4 rapidly establishes a 87:13 equilibrium of trans:cis lactols 6 and 11.
The cis lactol 6 is converted to trans lactol 6 by equilibration of a solution of 11 to the 87:13 trans:cis mixture and slow precipitation of the trans lactol 6 as the HCI salt. A simple conversion to the free base gives a solution of clean trans lactol 6, which is stable at 20xc2x0 C. for extended periods of time in the absence of strong bases or acids.
Although a number of the lactol isomers could potentially cyclize to bicyclic acetal 14, attempts to achieve this transformation under traditional acetal forming conditions resulted in complex mixtures. Treatment of a solution of 6 with tributylphosphine in THF at xe2x88x9230xc2x0 C. followed by the addition of DIAD and warming to ambient temperature gives crystalline bicyclic acetal 14.
As depicted in Scheme 4, the bicyclic acetal is quaternized in acetone with benzyl iodide at 50xc2x0 C. to yield 89% of salt 5. Regioselective Hofmann elimination proceeds by heating 5 in ethanol/water (3:1) with 1.1 equivalents of sodium hydroxide. The choice of iodide counterion for salt 5 allowed the direct isolation of the key vinyl ether intermediate 4 in 90% yield with rejection of the sodium iodide byproduct in the liquors. 
Reagents: (a)(i) aq. K2CO3, EtOAc (ii) Bu3P, DIAD, THF, xe2x88x9230xc2x0 C. to 20xc2x0 C., 86%; (b) BnI, acetone, 50xc2x0 C., 89%; and (c) 1.1 eq. NaOH, EtOH, H2O, 90%.
The (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine obtained in accordance with the present invention may be used as starting material in further reactions directly or following purification.
The starting materials and reagents for the subject processes are either commercially available or are known in the literature or may be prepared following literature methods described for analogous compounds. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures include crystallization, distillation, normal phase or reverse phase chromatography.
The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.